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ERNST BORIS CHAIN


CHAIN-FLOREY

Clinical Research Fellowships

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Introduction

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Sponsors and Advocates Professor Sir John Savill Professor Dame Sally Davies Professor Jonathan Weber Professor Dame Kay Davies Professor Sir Andrew McMichael Professor Chris Bunce Professor Sir Stephen O’Rahilly Professor Benjamin Chain

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Mentors Professor Irene Roberts Professor Charles Pusey Professor Anne Soutar

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Current Fellows Dr Allifia Abbas Newsholme Dr Eleanor Sandhu

Dr Andrew Innes Dr Antonio de Marvao Dr Parvin Begum Dr Jennet Williams Dr Elizabeth Byrne Dr Harpreet Lota Dr Amit Adlakha Dr Pratheeban Nambyiah

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Chain-Florey Scheme Details

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Alumni Dr Jonathan Bond Dr Tomoki Arichi Dr Jess Zhao Dr James Tomlinson Dr Amit Patel Dr Thomas Oates Dr Philip Webster


- Introduction -

Chain-Florey Clinical Research Fellowships offer medical graduates PhD opportunities in basic science laboratories at the MRC Clinical Sciences Centre In 1940 Howard Florey, Professor of Pathology at the University of Oxford, elevated penicillin from scientific curiosity to medical revolution. The collaboration between Florey and the biochemist Ernst Chain, supported by the practical knowledge of Norman Heatley, resulted in the isolation and first medical application of an antibiotic. Against the backdrop of World War II, Chain and Florey worked in a makeshift lab on a shoestring budget to unravel the secrets of penicillin.

drug discovery – stand as a tribute to the importance of the culmination of scientific endeavour and medical purpose. The Chain-Florey Fellowship Scheme brings medical graduates into the basic science laboratories of the MRC Clinical Sciences Centre (CSC) for three-year PhDs. The scheme is jointly funded by the MRC and NIHR through the Imperial BRC. Founded to spur the development of the next generation of world-class academic clinicians in the UK, the Chain-Florey Fellowships are an investment in the future of academic medicine. In previous decades, the relationship between science and medicine was arguably more transparent. This Fellowship reignites that longstanding collaborative tradition and provides medical graduates with the opportunity to undertake cutting edge fundamental research. Over three years in the CSC at the Hammersmith Hospital campus, Fellows develop their research skills and become as comfortable in the laboratory as they are on the ward. Close mentoring on both the clinical and scientific side ensures Fellows keep constant touch with their medical roots.

Alexander Fleming had stumbled upon the antibiotic potential of penicillin a decade earlier, with no inkling that his serendipitous discovery would lay the foundation for one of the most important medical advances of the 20th Century. Its power was only harnessed long after Fleming had abandoned the project. At a time when hundreds of lives were being lost every day, and a simple scratch could open the door to fatal infection, the combined expertise of a clinically trained pathologist and a biochemist changed the medical world. From the first miraculous demonstrations of the life-saving potential of penicillin in mice in May 1940, Ernst Chain and Howard Florey worked tirelessly to optimise its production, saving millions of human lives in the process.Their achievements were recognised in 1945, when they shared the Nobel Prize in Physiology or Medicine with Alexander Fleming.

Since the scheme’s inception in 2009, 17 Fellowships have been awarded and graduates have emerged ready to tackle clinical research questions with scientific precision. The experience affords Fellows the skills required to bridge the boundary between the clinic and lab, and drive medical science forward by studying the basics of health and disease. The first Chain-Florey Clinical Lectureship was awarded in 2014 and three more are planned for 2015.

It is in celebration of this unique collaboration that the Chain-Florey Clinical Research Fellowships are named. Antibiotics – perhaps the most important 20th Century

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PROFESSOR SIR JOHN SAVILL Chief Executive, Medical Research Council

CHAIN-FLOREY

The Chain-Florey scheme provides a fantastic opportunity for clinical Fellows to work with outstanding basic biomedical scientists at the MRC Clinical Sciences Centre. A key focus for MRC is to ensure that we are developing clinical academic leaders for the future who are grounded in excellent science, which they can link to their own clinical expertise. Such clinicians will play a critical role in developing knowledge and in ensuring translation of research findings into clinical situations.

Clinical Research Fellowships

SPONSORS & ADVOCATES

The MRC Clinical Sciences Centre is a unique discovery science laboratory embedded in Imperial College at the Hammersmith Hospital campus. This site has a long tradition of excellence in training clinicians in research and fostering cross-disciplinary collaborations. I and many of my colleagues have benefited enormously from the opportunities offered here. This scheme does a fine job of providing support for clinicians to gain robust scientific training while retaining relationships with their clinical mentors. There are many challenges in ensuring that both sides of this equation are delivered effectively and I am delighted with the success of this scheme in this regard. The Fellowship is a tribute to Professor Fisher, her team and of course to the Fellows who have embarked on this challenging but exciting course – it is a real pleasure to read their profiles, which reflect their commitment and enthusiasm – I wish them and all their successors well.

“ We are developing clinical academic leaders for the future ”

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- Sponsors Advocate & Advocates -

PROFESSOR DAME SALLY DAVIES Chief Medical Officer and Chief Scientific Adviser, Department of Health

Cell and molecular biological research powers advances in medical practice. The development of innovative medicine is reliant on fluent communication between scientists and doctors, and I am in full support of any scheme that fosters such collaboration. The training that these Chain-Florey Fellows receive in the basic science laboratories of the CSC will give them the perfect foundation to build careers that bridge the medical and scientific worlds. For these Fellows, keeping a firm grip on their clinical work while adapting to the novel challenges of academic life is challenging. I am strongly in support of mentorship schemes for young medical professionals, and this one is paving the way for great futures. The CSC is ideally located at the Hammersmith Hospital, and the clinical mentorship ensures that while they grow as scientists, the Fellows’ clinical skills don’t wane. Translational research in this country is an absolute priority, so fostering the links between the academics and practitioners of public health is vital. The Chain-Florey Fellows are developing strong relationships with worldclass biomedical researchers, and those bonds will last throughout their careers. Training our brightest clinicians in the art of fundamental science will be productive for practical medicine and biomedical science. This scheme is a shining example of the sort of career-shaping programme we are in need of.

“ This is paving the way for great futures ”

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Sponsors Advocates- Sponsorsand & Advocates

PROFESSOR JONATHAN WEBER Director of Research, Imperial NIHR BRC

“ We’re now using the ChainFlorey model as a template for many other schemes ”

I am a tremendous enthusiast of this scheme. Clinician scientists are in short supply, and are a very difficult group to train. With these posts, we agreed from the very beginning that they’d have to be held in a non-clinical lab, but that there would be a clinical mentor to bridge the divide. The Fellows would need strong mentoring, but with the right support it would be an extremely productive programme. The Clinical Sciences Centre is the jewel in the crown for Imperial College in terms of fundamental discovery biology, and we’re delighted to have this landmark scheme there. We’re now using the Chain-Florey model as a template for many other schemes. The advantage of these Fellowships is that clinicians and scientists learn to communicate. That communication is bilateral and durable. It can last a whole career, and is the key to this sharp end of translational medicine. This experience will give Fellows not only the skills, but also the tools to ask fundamental questions about clinical issues in the most rigorous way. The next step for the Chain-Florey Fellows is for us to be able to support the most successful in their post-doctoral careers, where the restrictions of clinical training challenge time for research. I am therefore delighted by the creation of the Chain-Florey Lectureships which will guarantee the research career progression of our most able Fellows.

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- Sponsors & Advocates -

PROFESSOR DAME KAY DAVIES Director, MRC Functional Genomics Unit, Dr Lee’s Professor of Anatomy, University of Oxford

“ This is a very exciting scheme, and incredibly important ” “I’ve always worked very closely at the interface between science and the clinic, and I don’t think that would be possible without having clinical training Fellows in the lab,” says Professor Dame Kay Davies. “When you get to the translational part of research, it’s a completely different way of thinking. That’s why the links between the clinician at the bedside, the basic scientist in the lab, and the clinical Fellows in between is very important indeed. A gap develops when basic scientists work on a problem in isolation, with no feeling for patients’ needs. You need a full understanding of the clinical phenotype before you can design a research strategy. A clinically trained person adds a tremendous amount. They bring with them a breadth of knowledge about the whole body that simply doesn’t exist without them. Of course, they have no idea of the basic science, so it really is an exciting two-way process. Some of them take to it like a duck to water, but not all. But they’re consistently very bright and highly motivated, so they more than make up for it. If you’re trying to practise and do research, you need a clinic within running distance, as it is at the Hammersmith. The Chain-Florey scheme is ideally placed to promote and support these Fellows. Now more than ever, it’s a challenge for a clinician to take time off during their career. But being in a lab broadens their outlook tremendously. This is a very exciting scheme, and incredibly important.”

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- Sponsors Advocate & Advocates -

PROFESSOR SIR ANDREW McMICHAEL Professor of Molecular Medicine, University of Oxford “This scheme is very attractive,” says Professor Sir Andrew McMichael. “I have great admiration for the Fellows. They’re doing the sort of things I’ve done in science, but at a far more advanced stage in their clinical training. They will emerge highly qualified both as scientists and clinicians, and there’s always a need for more of those people. When I first went into a non-clinical institution, it was fairly accidental. It was good to be able to concentrate entirely on learning how to do research without having to worry about going to clinics and ward rounds. Now clinical training has become much more formalised, and it can be hard to meet all the requirements to keep your clinical career on track and carry on your work as a scientist. However, this kind of scheme makes it possible. Getting people started on this career path gives them choices. If you’re really going to advance translational medicine, these are the people who will be the leaders. They are mature, highly motivated, and learn very quickly. They have skills that are very useful for practising as a scientist, but have respect for the full time clinicians dealing with patients. Being able to appreciate their difficulties is very important. My father was a Professor of Medicine at Hammersmith Hospital, so I grew up there. I’ve seen it develop, and with this top class research centre – the CSC – in the grounds it is a fantastic place to work. This whole scheme is excellent, and I wish all the Fellows good luck.”

“ Getting people started on this career path gives them choices ”

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- Sponsors & Advocates -

PROFESSOR CHRIS BUNCE Research Director, Leukaemia & Lymphoma Research

“ It exposes talented, motivated, well-trained individuals to stateof-the art technologies ” Schemes like the Chain-Florey Fellowship programme are essential in promoting translational research and addressing the cultural and language barriers between medicine and basic science. This pro-active initiative recognises that basic and clinical scientists often need some kind of encouragement to make contact with each other. Translational research has never been so strong. Today it’s possible for non-clinical and clinically trained researchers to build teams, make discoveries and personally drive them all the way to early-phase trials. It feels a bit like a ‘perfect storm’. In the past, translational research was viewed as perhaps not the highest of academic pursuits. Today the ethos across academia and industry is changing. Universities are being assessed not on publication prowess alone, but impact, the extent to which their research actually changes something. The pharmaceutical industry used to translate basic research. Today there is more of a desire to move the risk-taking into academic institutions, which empowers the whole movement towards translational medicine. Science is developing at such a great pace and the technologies that are evolving alongside are challenging. If the power of those technologies is not understood within the clinical community, there is a danger that the gap between basic and clinical science will open up again. The whole concept of a scheme like this is that it exposes talented, motivated, well-trained individuals to state-of-the-art technologies. This removes the fear of these technologies and empowers clinicians to embrace the possibilities so that they can be as at home in a lab as they are in a ward. This is really exciting.

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Sponsors - Sponsorsand & Advocates Advocates-

PROFESSOR SIR STEPHEN O’RAHILLY Director, University of Cambridge Metabolic Research Laboratories; and MRC Metabolic Diseases Unit I have benefited enormously from working in an environment where basic and clinical scientists rub shoulders with each other on a day-to-day basis. It really helps to foster cross-disciplinary thinking. It can bring to basic scientists clinical perspectives they may not have. The rigour and technologically innovative aspects of contemporary science can enlighten the clinician, who may not have previously appreciated what was possible. Some inquisitive and smart doctors have gone into science early after training in medicine and stopped practicing. Several such people such as Mike Brown, Joe Goldstein and Harold Varmus have won Nobel Prizes. What we have now is the opportunity to create a cadre of doctors whose science continues to be driven forward by their active clinical practice. The challenge is to retain clinical credibility and skills in a time of changing knowledge and pressures, while remaining at the scientific cutting-edge. The Hammersmith has been a Mecca for clinical science for many decades. What it’s done very well over the past 10 or 20 years is to strengthen fundamental science, ensuring it doesn’t lose links with the hospital. The raw brain-power of many of the young doctors that are attracted to undertake a period of research training is pretty formidable.When you combine that with some of the best scientists in Britain, then that’s a recipe for new ventures and points of light. This is the kind of environment that the MRC Clinical Sciences Centre and the broader Imperial College campus can provide.

“ The raw brain-power of many of the young doctors attracted to research training is pretty formidable ”

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- Sponsors Advocate & Advocates -

PROFESSOR BENJAMIN CHAIN Professor of Immunology, UCL

“ My father would have been very supportive of this scheme ”

“I once met the doctor who administered the first injections of penicillin, when he was a very old man,” recalls Professor Benjamin Chain, son of Ernst. “He said it was the most exciting moment of his life. He had a patient who he knew for sure would be dead by the next morning. He gave him this stuff, and the next day the patient was sitting up in bed, chatting. At that time, the link between scientists and doctors was so close. The barrier has only emerged relatively recently. These Fellowships are breaking down a wall that was never there before. My father felt very strongly that, in principle, it was very important to have close links between the clinic and lab. He thought that a lot of scientific discoveries of medical importance had come from medical observations. This scheme is something that he would definitely have been in favour of. He spent a lot of time saying that for the vast amount of progress in scientific understanding that he saw, the actual practical medical impact was relatively limited. It wasn’t translated, and it wasn’t clear how it could be. He felt doctors were important for showing scientists the implications for the medical world. He would have been very supportive of this scheme. My father and Florey were an early example of a very successful multidisciplinary approach. The medical profession is very resistant to change, while scientists constantly want to change things. These Fellowships bridge that divide between the conservative and progressive attitude, and get somewhere in between.”

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PROFESSOR IRENE ROBERTS PROFESSOR CHARLES PUSEY PROFESSOR ANNE SOUTAR

CHAIN-FLOREY Clinical Research Fellowships

“The Fellows have to learn a totally different way of thinking,” says Professor Irene Roberts. “They have to employ tremendously different skills to those that make you a successful clinician. The best part of being a mentor is seeing that change in them over the time of the Fellowship. They all approach it in different ways, but having the best scientific training at this early stage will give them flexibility. That bedrock on which they build their way of thinking about science is vital, no matter what they go on to do.”

MENTORS

“Working away in a very basic science environment, it could be easy for the Fellows to lose track of their clinical training and future careers,” says Professor Charles Pusey, Director of Clinical Academic Training at Imperial College. “Having clinical mentors allows the Fellows to discuss their progress and get impartial advice from a senior academic clinician. The success of mentoring depends on the relationship that develops between mentor and mentee. The frequency of meetings is variable, and driven by the Fellows. They generally find it helpful and reassuring to speak to an independent and experienced clinician who understands the clinical academic career path.” “Of course, the Fellows have two academic mentors, as do all PhD students at the CSC, but the clinical mentors are key to the success of this scheme,” agrees Professor Anne Soutar, Director of Postgraduate Studies at the CSC. “The Fellows are in a strange environment, completely out of their comfort zone. When they start it’s an absolute sea change for them.They go from being quite senior and responsible in the clinical arena to the bottom of the laboratory hierarchy. They’re suddenly working in an environment where they’re more expected to solve problems as an individual. Having this contact with the clinical world, and with someone who speaks the same language, is extremely important.”

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Current Fellows


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“ Learning the language of science has been a real eye-opener �

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DR ALLIFIA ABBAS NEWSHOLME • 2012 Fellow, Lymphocyte Development Group

Her model gene is named CDKN1C. “CDKN1C is expressed very widely in the brain, heart, kidney and adipose tissue,” reveals Allifia. “Mainly we know it’s important in neurobehavioural metabolism, even oncogenesis.” Mutations in the gene cause Beckwith-Wiedemann syndrome, which is characterised by an increased risk of tumour formation. “We believe the environment may influence the nature of expression of these genes,” explains Allifia. “So we will keep mice at different stages during their pregnancy on low-, medium- or high-protein diets. We want to see whether this causes a change in the expression of these genes from monoallelic to biallelic.”

“Learning the language of science has been a real eyeopener,” says Dr Allifia Abbas Newsholme, who is now close to completing her Chain-Florey Fellowship. “When I first heard Amanda Fisher and Rosalind John chatting about my project, I had absolutely no idea what they were talking about.” Allifia meets the challenge with a hunger for new knowledge and a willingness to step outside of her comfort zone. “When I first came across ‘epigenetics’ I went and bought a popular science book. I found the concept just mind-blowing. The idea of jumping into something so exciting and unknown was great.” Originally from Dubai, Allifia took her undergraduate degree at the University of Leeds, and an intercalated BSc in immunology at the Royal Free. She has two years further training in her chosen specialty of Nephrology at the London Deanery. “When I came to meet CSC scientists and consider the project options, I could not decide on a project. “Meeting with Amanda and getting a sense of how she sees things was enough to convince me.”

First she had to make a genetic construct in which a luciferase reporter was added into the silent CDKN1C allele. This allows gene expression to be visualised. “It took me a year to make the construct,” she admits. “But now we can image the genes in real time. If the silent allele becomes active the luciferase reporter will switch on too.” Using constructed embryonic stem (ES) cells to generate mice, Allifia is hopeful that she can detect tissues showing biallelic expression of Cdkn1c.

Allifia is looking at imprinted genes which are expressed in monoallelic fashion. “These genes are important in neurobehavioural development and are implicated in longterm chronic diseases,” she reveals. “My project is to devise a system to image changes in their expression.” She is using a range of molecular biology techniques including cloning, imaging and working with mice. “It involves lots of skills that are really important if I’m to have a career in basic science.”

Allifia is surprised at how far she has come during her Fellowship. “It’s an uncomfortable thing to unfetter yourself from your clinical preoccupations, but now I’m beginning to talk the language of science.”

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DR ELEANOR SANDHU • 2012 Fellow, Neurophysiology and Metabolic Signalling Groups “It’s fun being involved with setting up a new technique and then getting it to work,” says Dr Eleanor Sandhu, who is now approaching the end of her Chain-Florey Fellowship. Working with Mark Ungless (Neurophysiology) and Dominic Withers (Metabolic Signalling), she is investigating what networks are involved in regulating salt appetite. “I’ve been very lucky that I’ve had the freedom to create my own project.” With an undergraduate medical degree from the University of Cambridge and clinical training at UCL, she moved to North Thames to specialise in Nephrology. Eleanor comes to the CSC with only a little former lab experience.

“ It’s fun being involved with setting up a new technique and then getting it to work ”

As a doctor Eleanor has worked with patients who require dialysis because their kidneys no longer work. “People with

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- Fellows -

heart failure salt retain,” she explains. “They should be on a low-salt diet but seem to have an abnormal salt preference making it very difficult for them.” Patients with kidney failure have a similar problem. Regular dialysis relieves these patients of the water, salt and byproducts that they are unable to excrete. “But some of them just can’t stick to the low-salt diet,” says Eleanor, “so they drink too much. The excess fluid can put huge pressure on the circulatory system and heart, and they often end up with pulmonary oedema.”

– to make them salt deplete.” The mice then feed on jellies with differing salt concentrations. “Then I can measure their salt appetite and preference.” With mice genetically modified to express Cre in dopamine neurons, Eleanor is using a virus to transfect a light sensitive channel into the dopamine neurons of the VTA. “The Cre-expressing cells then also express the light-sensitive channel. I then embed a fibreoptic into the VTA.” This allows dopamine neurons to be illuminated and stimulated in situ so that their effect on behaviour can be studied.

Finding out what makes salt attractive could reveal a way to help these patients. Previous studies have suggested that dopamine neurons are involved. The Ventral Tegmental Area (VTA) of the brain, where the dopamine neurons sit, is tied up with addiction, wanting and reward, so Eleanor’s project is probing this region of the brain with a view to uncovering the networks at play in driving salt seeking behaviour. “From the survival point of view, reward pathways have developed in our brain to drive us to get things we need like food, salt and water,” says Eleanor, “so it looks like drugs of addiction hijack the normal reward system.”

The optogenetic system has allowed Eleanor to see what happens to salt appetite when dopamine neurons are stimulated. “Interestingly my results went in the opposite direction to that which I expected. Based on the results of the optogenic and pharmogenetic experiments I am now using electrophysiology to test the hypothesis that salt appetite is a withdrawal state with hypoactive dopamine neurons. This is similar to alcohol withdrawal.” Eleanor hopes that there might be help for dialysis and heart failure patients if research can uncover a way to reduce their salt appetite through some form of manipulation.

Eleanor explains how she is approaching the research. “I induce a salt appetite in mice using a diuretic – furosemide

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- Fellows -

DR ANDREW INNES • 2012 Fellow, Cellular Senescence Group

“When I first learned about my project and saw the others presenting in the lab meeting, I was terrified,” admits Dr Andrew Innes. “I thought there’d be no way I could do these experiments.” Now close to finishing his Fellowship, Andrew is taking lab life in his stride. “Suddenly you realise you’re doing it with everyone else, and you’ve just finished a genome-wide screen.” After a nine month Academic Clinical Fellowship at Imperial College with Francesco Dazzi, Andrew approached the bench with a firmer grounding in basic research than many other Chain-Florey Fellows.

gene so that we can figure out which ones are important. We’re using next generation sequencing to identify the most important ones.” The project is coming to a close, but Andrew hopes the findings will be relevant to his clinical interest. “Senescence is well known for its role in controlling cancers, but its role in fibrotic disorders is less well understood,” he confirms. “I’m interested in post-transplant fibrotic disease, specifically Graft Versus Host Disease (GVHD).There’s a lot of evidence that this mimics autoimmune disease, but there is also evidence that could link it to senescence.”

After training in Dundee, Glasgow and Manchester, Andrew moved to London in 2008 to specialise in Haematology. “I’m already almost four years into that,” he reveals, “so I’ve only one more year to do.” An intercalated BMedSci in Pharmacology and Neuroscience gave him his first taster of basic science. “I did a project looking at the anti-platelet effect of chocolate.” Discovering that dark chocolate inhibits platelet clotting cemented Andrew’s desire to pursue a career in clinical research.

The project has introduced Andrew to a host of new techniques. “I’d done some PCR and flow cytometry before and a little bit of cell culture,” he says,“but I’d never done any RNA knockdown-based techniques, confocal microscopy or Western blots.” Faced with a steep learning curve, which introduced him to lentiviral and retroviral biology, among other things, Andrew was undaunted by the challenge. “Maybe I was extra prepared because former Fellows had warned me how tough it would be. You don’t get the immediate self-gratification that comes with working on the ward, making sick people better,” he adds, “you have to wait weeks for experimental results.”

Working with Jesús Gil at the CSC, the goal is to uncover the genes that regulate replicative senescence. “When you culture cells, they only grow for a certain amount of time and then stop growing. Like the cells in our bodies, they remain metabolically active and can still influence cells around them.” Andrew’s project has looked at what controls senescence in the natural ageing process. “We’re using a genome-wide viral screen to knock down every known

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“ Suddenly you realise you’re doing it with everyone else, and you’ve just finished a genome-wide screen ”

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DR ANTONIO DE MARVAO • 2012 Fellow, Molecular Cardiology and Integrative Genomics and Medicine Groups “The Chain-Florey Fellowship scheme was the obvious choice for me when I decided I wanted to do research,” says Antonio. Born and bred in Lisbon, he explains his welldeveloped Scottish lilt,“I moved to Glasgow when I was 17.” Graduating from Glasgow Medical School in 2007 he was to remain in Scotland for two further years to complete house officer training. Antonio then made the move to London in 2009 to complete his core training at Imperial College London.

“ Ultimately, we’d like to understand how specific genes and gene pathways affect disease progression ”

With no former experience in a research environment, Antonio was inspired to visit the CSC when he rubbed shoulders with colleague and Chain-Florey Fellow, Dr Phil Webster, at the Hammersmith campus. A conversation with CSC Director, Amanda Fisher, and Director of Postgraduate

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Studies, Anne Soutar, led to a decision to carry out two months work experience with James Leiper (Nitric Oxide Signalling Group), to help equip Antonio with basic lab skills, and give him a taster of what was to come. He was hooked, although he says of the Fellowship, “This is the hardest thing I’ve done in my career.”

For each volunteer, next generation targetted DNA sequencing is being performed on a panel of 200 genes, which have previously been linked to cardiomyopathies. Thanks to additional support from the BHF, the Wellcome Trust and the NIHR, a large bioinformatics and sequencing infrastructure was created at Imperial with Professor Stuart Cook providing the link to clinical cohorts from the Brompton NHLI site. The goal is to identify common and rare genotypic variants that influence the shape and function of the heart. Antonio sums up: “Ultimately, we’d like to understand how specific genes and gene pathways affect disease progression, so we can give patients an accurate prognosis and choose the most appropriate treatment.”

Working with systems-geneticist Enrico Petretto (Integrative Genomics and Medicine Group), clinicianscientist cardiologist Stuart Cook (Molecular Cardiology Group Cardiovascular Magnetic Resonance Imaging and Genetics) and radiologist Declan O’Regan (MR Facility), Antonio’s clinical interests are well matched to his research project. “I’m a cardiologist, and am particularly interested in the use of imaging as a tool to investigate cardiac patients and guide their treatment.” His PhD involves looking for genes that influence heart shape and function. “We’re analysing a cohort of 1,750 healthy human volunteers,” he explains. “Each volunteer is being scanned with traditional cardiac MRI techniques and state-of-the-art 3D approaches. Scans will help create a much more detailed 3D model of the heart than has previously been possible.” After having manually created 20 cardiac atlases that provide prior anatomical knowledge he can now use automated software to analyse new scans. “Each 2mm3 point (pictured) in these high resolution scans is labelled as either muscle or blood and given a co-ordinate (XYZ) in space. We then co-register each point with corresponding points in other hearts. Finally we pool the data for all 1,750 people into one 3D model.” With the thickness and function of the heart muscle measured at thousands of different points, the model harnesses a powerful and detailed dataset. “We can then look at these data any way we want,” says Antonio, “to explore the effects of environmental or genetic factors on the heart.”

Cardiac atlas

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DR PARVIN BEGUM • 2012 Fellow, Gene Regulation and Chromatin Group

“The best thing about the Chain-Florey Fellowship is having the time to concentrate on a completely new area,” says Dr Parvin Begum, now two years into her PhD with Niall Dillon in the CSC’s Gene Regulation and Chromatin Group. “As a doctor you can do some clinical research on the side of your day to day work, but to have robust scientific training in a place like this is a great opportunity.” With an NIHR Clinical Academic Fellowship under her belt, Parvin comes to the institute with some previous lab experience. “I had a little time in the lab as part of my NIHR fellowship but it was enough to give me the exposure I needed to consider a basic science PhD rather than a predominantly clinical one.”

important in cancer,” explains Parvin. She is trying to find out more about the transcriptional regulation of this gene. “Cancer patients with tumours that overexpress Aurora B have a poor prognosis compared to those who don’t but we know little about the mechanisms underlying this,” Parvin says. “I want to look specifically at the epigenetic effects of Aurora B in lung cancer.” Parvin has had to get to grips with lab techniques including cloning, transfection, Western blotting, chromatin immunoprecipitation, RNA analysis and gene reporter assays. “Thanks to my former lab stint, I didn’t feel too uncomfortable at the bench,” she says. “But it’s a completely new venture. There’s a lot to learn. You do some basic science in your medical degree, although nothing this in depth.” During her first two years she’s been using mouse cells. “We had ChipSeq data for that, so I’ve been cloning and modifying parts of the genome that potentially control the Aurora B kinase gene in mouse to see what’s important. I am now focusing on the human system and starting experiments with lung cancer cells.”

A year’s speciality training in respiratory and general medicine has led to her clinical interest in lung cancer. “I’ve always been interested in genetics, and then started to become really interested in epigenetics. That combination of interests brought me to the CSC at Imperial, because there is such a strong epigenetics section here.” She is investigating the role of a mitotic kinase in lung cancer. “The kinase is known to be involved in cell cycle regulation, having important functions in mitosis. Recently the lab discovered that Aurora B kinase also plays a role in regulating quiescence.” Quiescence describes a resting state where cells are not actively dividing but retain the ability to re-enter the cell cycle. “It’s important in maintaining tissue homeostasis.”

“It’s fascinating to be able to physically manipulate gene sequences to try to answer questions you’re interested in.” In the future she hopes to continue with research. “It’s great being at the CSC. There’s so much expertise and technology available if you want to use it.”

Parvin is looking at whether Aurora B may be involved in mediating the choice between cells continuing to cycle or entering quiescence. “Deregulation of that process may be

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“ It’s fascinating to be able to physically manipulate gene sequences to try to answer questions you’re interested in ”

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“ It’s incredibly challenging, but doable ”

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DR JENNET WILLIAMS • 2013 Fellow, Cellular Stress Group

slow tumour growth,” explains Jennet. “But the evidence as to whether AMPK is a friend or foe to cancer is conflicting. It may well do different things in different types of cancer or at different stages in the disease.”

“As a Medical Oncologist you’re familiar with reading about and interpreting Western blots but when you actually do your own for the first time it feels like a really big achievement,” says Jennet Williams, who started her ChainFlorey Fellowship in March 2013.

Having completed one fellowship already at The Wellcome Trust Centre for Human Genetics in Oxford, Jennet was no stranger to the lab. “The Chain-Florey Fellowship has provided an excellent opportunity for me to combine basic science training with my interest in cancer metabolism,” she says. One of the biggest challenges of the Fellowship has been adapting from being one of the most experienced people in her job as a Medical Oncology Registrar to the least experienced person in the lab – and therefore being dependent on other people, instead of them upon her. But she enjoys lab work and hopes to continue her current line of research.

Jennet studied medicine in Wales before heading to London’s Hammersmith Hospital. Caring for cancer patients as a Palliative Care Registrar in Bristol, she developed a desire to specialise in Medical Oncology. During her Academic Clinical Fellowship at Imperial College London she heard about the Chain-Florey scheme. Jennet now works in the Cellular Stress Group with Dave Carling, whose research aims to understand the regulation and roles of AMPactivated protein kinase (AMPK), a key governor of energy metabolism. She is fascinated by a phenomenon known as the Warburg effect – the observation that cancer cells metabolise glucose differently to normal cells. Although first discovered in the 1920s, the significance of the Warburg effect was neglected until very recently, when ‘reprogrammed energy metabolism’ was added to the original six hallmarks of cancer. Given the key role that AMPK plays in metabolism and the metabolic changes that occur in tumours, AMPK is likely to be important in cancer so she’s looking specifically at the effects of activating AMPK in the liver during the development and progression of hepatocellular cancer.

“You know the work you’re doing in the lab is going to generate results, and whether positive or negative, they’ll answer questions. Cancer research is evolving rapidly and much of the progress made has been at the basic science level. As a specialty, Medical Oncology really lends itself to a career as a clinician scientist. It’s incredibly challenging, but doable.” Jennet has already got results and some of her findings have been surprising. “Our model hasn’t behaved as we expected it to, given what we know about AMPK, but that’s exciting – it suggests things are more complex than we originally thought and that there’s more to investigate.”

“If AMPK inhibits cancer, then you could use drugs that activate AMPK in patients with hepatocellular cancer to

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- Fellows -

DR ELIZABETH BYRNE • 2013 Fellow, Cell Interactions and Cancer Group After completing an Academic Clinical Fellowship at Imperial College London, Dr Elizabeth Byrne received a tip off from her supervisor about the Chain-Florey scheme. Her previous fellowship focussed on haematological malignancies.“The main goal was to characterise microRNA expression in lymphomas,” she reveals.“We wanted to know whether they could offer prognostic guidance. Lymphomas can be quite difficult to diagnose and treat, but changes in microRNA expression could help to better group patients offering more targeted treatments and a clearer prognosis.”

“ I’ve been getting to grips with RNA extraction, which is quite challenging because the RNA degrades so quickly ”

Elizabeth was sure she wanted to do something completely different for her PhD at the CSC. With a project looking at Schwann cell de-differentiation she has certainly ticked that box. Now a year into her Chain-Florey Fellowship – with

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- Fellows -

Simona Parrinello (Cell Interactions and Cancer Group) – she is relieved to be getting her first results. “When I first spoke to Simona about the project I thought ‘I should be able to do this in a few months’,” she remembers. “But it’s been a very slow process. At one point I thought it wasn’t going to work, but now it seems we’re starting to get somewhere!”

suspension, she uses Flourescense-activated cell sorting (FACS) to extract the Schwann cells. At that stage the challenge is to get enough good quality RNA to sequence. “I’ve got to the point where I can isolate the Schwann cells and get RNA of good quality in sufficient quantities. So I’ve reached a point where we can start sequencing now, which has just happened in the last few weeks.”

Schwann cells surround the axons of peripheral nerves, producing myelin, which helps insulate the nerve fibre to facilitate signal conduction. “When you get an injury to a peripheral nerve, the Schwann cells de-differentiate. They go back into a stem-cell like progenitor state,” explains Elizabeth. She is trying to characterise the repair process from the perspective of the transcriptome. By measuring the levels and diversity of RNA inside Schwann cells after injury she hopes to build up a picture of the molecular changes that result from nerve damage. “I’ve been getting to grips with RNA extraction, which is quite challenging because RNA degrades so quickly.”

While Elizabeth is on track with her project, she is also expecting her second child. “I should be back by January of my final year though, and I’ll be working up until 38 weeks if I can!” Once she has completed her project she plans to resume her clinical work in histopathology on a parttime basis to give her enough time to write up. “I think my specialty is quite compatible with a career in basic research. Histopathology and research go hand in hand. Since you’re looking at changes in different tissues during disease, you naturally want to know more about the underlying molecular process.” Elizabeth has already decided she wants to specialise in neuropathology once she finishes, so her PhD will provide her with a good grounding in this research arena.

In order to isolate the cells, Elizabeth is using a mouse model that has red fluorescent Schwann cells. After making a cell

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- Fellows -

DR HARPREET LOTA • 2013 Fellow, Nitric Oxide Signalling and Single Molecule Imaging Groups

“I’ve always wanted to do a PhD,” reveals Dr Harpreet Lota, who took up her Chain-Florey Fellowship a year ago with James Leiper (Nitric Oxide Signalling Group) and David Rueda (Single Molecule Imaging Group). “I wanted to understand the underlying pathogenetic mechanisms of the diseases that as a doctor I have been coming across daily.” Harpreet finished her fourth year as a respiratory registrar at North West Thames after completing her medical degree at Imperial College London.

a normal feature of wound healing, as Harpreet points out, “the process goes wrong in pulmonary fibrosis.” “I’m working on a human alveolar epithelial cell line, currently using an iNOS (inducible nitric-oxide synthase) inhibitor to manipulate the tail end of the pathway to see if I can alter the EMT process.” The initiative is geared towards finding a therapeutic application down the line. “Once I’m done with the cell line, I’ll be able to take the work into a mouse model using the well-known bleomycin murine model of pulmonary fibrosis.” The project requires Harpreet to learn many new techniques including PCR, Western blots, mass spectrometry and cell culture. “I’d done a little bit of PCR before, but everything else is new!”

“When I was a respiratory registrar at the Royal Brompton Hospital, I became particularly interested in fibrotic lung disease, which led to a short-term project at the National Heart and Lung Institute (NHLI) looking at single nucleotide polymorphisms in the hypoxia-induced factor 1 alpha (HIF1A) gene in patients with systemic sclerosis.” This first taste of basic science confirmed Harpreet’s desire to pursue opportunities to carry out research. “I came across an advert for the Chain-Florey Fellowship scheme and thought I would apply.”

IPF is a chronic progressive, fibrotic lung disease with no known cure. “We think it starts from an unknown alveolar epithelial cell injury,” explains Harpreet, “which leads to aberrant wound healing.” The disease is characterised by a honeycomb fibrosis of the lungs, which leads to restricted lung function and severely impaired gas exchange. “Patients get very breathless since thickening and scarring reduces the amount of oxygen that can pass into the blood vessels in affected regions of the lung.” While there are some new therapeutic agents that can potentially slow disease progression, there is no known way to reverse the damage once it happens. “And we don’t know anything about how the DDAH/NO pathway operates in EMT,” says Harpreet. While her project will help to characterise a well-known pathway in a novel context, there is also the possibility of therapeutic benefit for the 3 in 10,000 people that will develop IPF.

Harpreet’s PhD thesis is borne out of her clinical interest. “I’m trying to identify the mechanistic pathways linking dimethylarginine dimethylaminohydrolase (DDAH) activity to Idiopathic Pulmonary Fibrosis (IPF).” The DDAH enzymes help to mop up the methylarginines that are produced when proteins are naturally degraded in our cells. Recent research has linked increases in DDAH with epithelial cell proliferation. “At the moment, I’m focussing on epithelial to mesenchymal transition (EMT),” explains Harpreet. During EMT, epithelial cells take on a fibroblastic phenotype and lay down extracellular matrix. While this is

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“ I’d done a little bit of PCR before, but everything else is new! ”

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- Fellows -

DR AMIT ADLAKHA • 2014

DR PRATHEEBAN NAMBYIAH • 2014

Amit completed medical school in Edinburgh and foundation training in Glasgow, before moving south to University College Hospital, London. He is now dual-training in Respiratory Medicine in North West Thames and Intensive Care Medicine in the Oxford Deanery. Registrar placements in HIV and Infectious/Tropical Medicine stirred up Amit’s interest in respiratory infection, and a placement on the Transplant team at Harefield Hospital led to his current area of research – infectious complications following lung transplantation. Amit started his Fellowship in February with Boris Lenhard in the Computational Regulatory Genomics group, and Darius Armstrong-James in the Fungal Immunobiology group.

Pratheeban recently finished his training in anaesthesia, with a sub-specialty interest in paediatric anaesthesia. Before and during university he worked as a research assistant in a variety of labs, which first sparked his interest in science. He will join André Brown’s lab in the Behavioural Genomics Group to develop a project on anaesthesia-induced neurotoxicity in the developing brain. His other non-clinical interest is in simulation and education. He has recently completed a fellowship in simulation in Ottawa, Canada, and is still involved with research there. He has an open mind about where all this will lead, but hopes that it will be to an interesting life surrounded by intriguing people, and perhaps the chance to find something out.

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- Fellowships & Lectureships -

CHAIN-FLOREY CLINICAL FELLOWSHIPS

CHAIN-FLOREY CLINICAL LECTURESHIPS

ELIGIBILITY CRITERIA

RESEARCH AREAS

• Practicing Medic in training in the UK

• Renal medicine

• Hold a National Training Number and be eligible for ‘OOPE’ (Out of Programme Clinical Experience for Postgraduate Doctors in training)

• Cardiovascular sciences • Endocrinology and Metabolism • Haematology

• Would normally have passed Membership exams Chain-Florey Clinical Research Fellowships are for medical graduates pursuing a career as an academic clinician. Fellows carry out their research in one of the MRC Clinical Sciences Centre’s world-leading basic science groups. Chain-Florey projects must involve human tissues or samples or be otherwise related to human disease of relevance to the Academic Health Science Centre strategy. Fellows have 3 years to complete their PhD before returning to their postgraduate clinical training.

Chain-Florey Clinical Lectureships provide support for clinician scientists who have already successfully completed a PhD or post-doctoral fellowship in basic science. The first Lectureship was awarded in 2014 to Dr James Tomlinson in renal medicine. Additional Lectureships will be awarded in cardiovascular sciences, endocrinology and metabolism and haematology. As a world leader in basic science, the MRC Clinical Sciences Centre strengthens its support for clinical academia through the Lectureship programme.

The CSC is looking for candidates with a genuine interest in doing scientific research, and an open and enquiring mind. Previous laboratory experience is helpful but not essential. Fellows will receive excellent scientific training on an interesting project within an internationally competitive research institute. This will equip them with the scientific skills and experience needed for a high-flying academic career in clinical research. The CSC plans to offer 3 posts each year to European Economic Area nationals.The posts are jointly funded by the MRC, Imperial College London and the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust. For further information, visit www.csc.mrc.ac.uk

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CHAIN-FLOREY Clinical Research Fellowships

ALUMNI

DR JONATHAN BOND • 2009-2012 “The chemotherapy used for leukaemia treatment hasn’t changed much in the last 40 years,” explains Dr Jonathan Bond – the first ever Chain-Florey Fellow. “I’m looking at very immature leukaemia cells to understand why normal blood cell development gets blocked and causes leukaemia.” Jonathan is particularly interested in the role of the Core Binding Factor (CBF) protein in these immature leukaemias. “Around 20% of myeloid leukaemias have abnormalities in CBF,” he explains, “so I’m currently exploring how genetic abnormalities in this transcription factor affect early blood cell development.” Jonathan works in Elizabeth Macintyre’s lab at l’Hôpital NeckerEnfants Malades supported by a Kay Kendall Leukaemia Fund Intermediate Research Fellowship. Soon he hopes to take up a clinician scientist role in London.

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- Alumni -

DR TOMOKI ARICHI • 2009-2012

DR JESS ZHAO • 2010-2013

Since completing his Fellowship, Dr Tomoki Arichi remains committed to clinical academia, and was appointed an NIHR Clinical Lecturer at King’s College London in 2012. This post has given him the funds and time to build on the MRI work he started during his PhD and has led to the award of a Starter grant by the Academy of Medical Sciences in 2014. The experience gained in Imaging Sciences at the CSC was vital to his fundamental understanding of the techniques required for this work. Currently he is developing functional MRI techniques to study activity in the developing brain of infants born prematurely and affected by stroke. He also holds a visiting position in the Bioengineering Department at Imperial College, where they are developing new robotic tools for assessing infant motor function.

“I would definitely recommend this Fellowship to doctors with an interest in basic science. It provides an excellent opportunity to carry out exciting research supported by experts in their fields.” Dr Jess Zhao completed her PhD research project in the Cellular Stress Group with Dave Carling. “The Chain-Florey Fellowship has given me the opportunity to work in a fantastic lab and has confirmed my desire to become an academic clinician. Finding the right balance of clinical and research work has been more challenging than I expected, and it’s still something I’m working on.” Having returned to complete her core medical training, she hopes to pursue a career in academic medicine in the future, and is particularly interested in specialising in care for the elderly.

Tomoki is currently a Clinical Lecturer in Paediatric Neurology at King’s College London.

Jess is currently a trust doctor in the stroke unit at Charing Cross Hospital, Imperial College Healthcare NHS Trust.

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- Alumni -

DR JAMES TOMLINSON • 2010-2013

DR AMIT PATEL • 2010-2013

Dr James Tomlinson was awarded his PhD in early 2014. As a nephrology specialty trainee, he studied nitric oxide (NO) signalling in kidney physiology and disease. Using in vitro and transgenic in vivo approaches, James discovered that enzymes acting to increase NO biosynthesis, the dimethylarginine dimethylaminohydrolases (DDAHs), have a significant impact upon both acute inflammatory and chronic fibrotic kidney disease. James has since been awarded a Clinical Lectureship under the Chain-Florey scheme, enabling him to develop this work further while completing his clinical training at Hammersmith Hospital. In the future, he hopes eventually to lead his own research group.

Dr Amit Patel started his Chain-Florey Fellowship in 2010 with Professor Luis Aragón in the Cell Cycle Group. Using a yeast model system of DNA damage and repair he found that a DNA double strand break during telophase is repaired using homologous recombination despite segregation of sister chromatids, making repair inherently mutagenic. Amit completed his PhD in 2013 and returned to clinical training in stem cell transplantation at Imperial College Healthcare NHS Trust before moving to the Royal Marsden NHS Foundation Trust in 2014. Amit is a Specialist Registrar in Haematology and Intensive Care Medicine in West London. He continues translational research on cellular therapy, sepsis and cancer, as an NIHR Clinical Lecturer at the Institute of Cancer Research and an Honorary Clinical Lecturer at Imperial College London.

James is currently completing his registrar training in renal medicine at the Imperial College Healthcare NHS Trust at Hammersmith Hospital.

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- Alumni -

DR THOMAS OATES • 2010-2013

DR PHILIP WEBSTER • 2011-2014

Dr Thomas Oates has just been awarded his PhD. He has no doubt that three years in research has benefitted his clinical practice. “I feel more able to take an analytical approach to clinical questions based on my scientific training,” he says. Specifically Tom looked at single base resolution analysis of DNA methylation in crescentic glomerulonephritis using bioinformatics methods. “This now means I can tackle clinical projects with much greater ease than previously. Genomic technologies and analysis are seen as a key part of the future of medicine, and my first hand insight into this fast-expanding topic will be extremely useful in appraising the introduction of these techniques into the NHS.”

“The Chain-Florey Fellowship is an excellent opportunity to acquire solid, basic science training for any doctor intending to have a career in academia,” says Dr Philip Webster, who completed his PhD with Anthony Uren in the Cancer Genomics group. Phil looked at the kinetics and genomics of BCL2-driven lymphoid malignancies, focusing on B cell apoptosis. “I wanted to gain knowledge, experience and learn new techniques within the genomics of the immune system and then apply this to my interest in autoimmune diseases.” Having returned to his speciality training in renal medicine, he intends to pursue an academic career path. Phil is currently renal registrar at Imperial College Healthcare NHS Trust.

Tom is currently Specialist Registrar in Renal Medicine & Transplantation at the Imperial College Renal and Transplant Centre at Hammersmith Hospital.

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Inside front cover image courtesy of Professor Benjamin Chain. Inside back cover image Š National Portrait Gallery, London. Produced by the Grants, Engagement and Communications Facility, MRC Clinical Science Centre. Printed by ScanPlus.


HOWARD WALTER FLOREY


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